Successful transition from fetal to neonatal life depends upon the integration of key neuroendocrine systems: sympathoadrenal, thyroid and adrenocortical. The developmentally programmed changes which occur in these systems represent key maturational signals for the developing mammalian fetus. Pharmacologic manipulation of these systems has evolved as a strategy to induce maturation in the preterm fetus. Antenatal corticosteroid treatment is a clinical routine to accelerate fetal lung maturation in infants at risk for preterm delivery. In contrast, there is less information on the effect of antenatal corticosteroids on postnatal function of other major organ systems. Our central hypothesis is that pharmacologic fetal maturation strategies which are clinically successful have significant maturational effects on these three neuroendocrine systems. Acceleration of neuroendocrine maturation in turn will result in improvements in postnatal adaptation, thus facilitating a reduction in non-pulmonary neonatal morbidity and mortality. To test this hypothesis, we will compare physiologic adaptation to extrauterine life in preterm, newborn fetal sheep which have been treated with a variety of maturational agents (corticosteroids, thyroid hormones, EGF) alone and in combination. Mechanisms for the action of these agents at the level of circulating hormones (catecholamines, thyroid hormones, cortisol, prolactin), receptors (adrenergic receptors, nuclear thyroid receptors) and second messenger systems (adenylyl cyclase) will be investigated. The doses, treatment strategies and routes of administration have been chosen to provide the most clinically relevant results. Parallel studies are proposed in fetal/newborn sheep and in human preterm infants enrolled in an ongoing clinical trial of the effect of betamethasone alone and in combination with thyrotropin releasing hormone.
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